Esophageal cancer is a common malignancy in the United States and worldwide, and yet, carries a dismal prognosis with 5-year survival of less than 30% for early stages and less than 10%for advanced stages. Progress has been hampered by the lack of robust, reproducible models. To that end, we have developed innovative models in organotypic culture and in animals that phenocopy, for the first time, human esophageal squamous cell cancer (ESCC). These models emphasize the role of critical oncogenes and tumor suppressor genes. We hypothesize that the interplay of the EGFR oncogene with the dysregulation of the p53 and p120-catenin (p120ctn) tumor suppressor genes alters the tumorigenic potential of esophageal cells, thereby resulting in increased cell migration and invasion. Furthermore, we hypothesize that changes in the mesenchymal compartment of the esophagus occur during tumorigenesis whereby tumor activated fibroblasts interact in a paracrine manner to induce increased esophageal tumor cell migration and invasion. These interdependent hypotheses will be pursued by the following interrelated Specific Aims to understand the esophageal tumor microenvironment: (1) To investigate the role of p120ctn, a functional interactor with EGFR, in fostering esophageal cancer cell migration and invasion in the tumor microenvironment. Specifically, we will assess the effects different isoforms and phosphorylation mutants of p120ctn and understand the role of p120ctn in esophageal tumorigenesis using genetically defined organotypic culture and in vivo models; (2) To investigate how EGFR overexpression and p53 mutation cooperate to induce esophageal tumorigenesis in similar models with an emphasis upon the differential biological properties of structural p53 mutants found to occur in esophageal cancer; (3) To identify critical signaling pathways in activated fibroblasts involved in paracrine signaling to tumor cells that increase tumor cell migration and 'nvasion in the microenvironment. These collective approaches provide a platform for exciting, new targeted therapeutic approaches in concert with Projects 2 and 3 that are primed to overcome resistance of esophageal cancer to current therapy. Project 1will continue to utilize the outstanding core facilities. RELEVANCE (Seeinstructions): This Project focuses upon the interplay of the EGFR oncogene with the p120ctn and p53 tumor suppressor genes in fostering esophageal squamous epithelial transformation and the interaction with stromal fibroblasts, and has unraveled new models and insights. The findings have relevance in combinatorial therapy of esophageal cancer and other squamous cell cancers.